Our exciting experimental data generated over the last several years indicate the novel role that glutamate receptor mediated neurogenic events play as a key factor in inflammatory nociceptive processes. Glutamate receptor antagonists given in the spinal cord dorsal horn eliminate half of the joint swelling induced in rat inflammation models. Our recent finding that knee injections of glutamate receptor agonists increase joint blood flow, plasma/protein extravasation, joint swelling, and nerve activation intimates peripheral glutamate involvement. This may account for glutamate increases in inflamed joints in animal models and in clinic patients with active arthritis. In clinical samples, glutamate is high in joints with active arthritis and is independent of levels in the patients' other joints or in the plasma. Preliminary data presented here for an in vitro model suggest that glutamate release by small, nociceptive afferent fibers in the knee joint can directly initiate inflammatory cascades through stimulation of tumor necrosis factor (TNF_alpha) release since specific glutamate agonists added to synovial cell cultures increase TNF_alpha levels detected in the culture supernatant. Secondly, the observation that the NMDA glutamate receptor subunit NR1 can translocate to the nucleus in both the in vitro and in vivo models suggests that a novel signal transduction event may be involved. Together these findings led to the hypothesis for the studies proposed that glutamate receptor_mediated molecular events play a critical role in initiation of inflammatory cascades. Specific Aims designed for these studies include the following: Specific Aim 1. To determine if the NMDA glutamate receptor subunit NR1 can translocate to the nucleus. Specific Aim 2. To identify key signaling pathways regulating nuclear translocation of NMDA glutamate receptor subunit NR1. Specific Aim 3. To determine if the nuclear NR I translocation is associated with glutamate_induced TNF_cc release from synoviocytes. These studies will seek mechanisms that may lead to novel translational approaches to abrogation of the inflammatory state through pharmacological interventions directed at inducible, glutamate receptor_mediated signal transduction pathways since use of glutamate receptor antagonists is not a clinical option. These studies will utilize anatomical, biochemical, and molecular methods to examine models of arthritis in rats and human clonal, synovial cultures. Since case studies in the literature report recovery of joint integrity in some cases after stroke, these studies seek a better understanding of the interactions of neurogenic and immune processes in the hope that reversal of joint inflammation for patients is possible.